This Program Project will direct the research of three academic research laboratories and our industrial partner GlaxoSmithKline (GSK) toward the development of antimicrobial compounds for the treatment of malaria infections. The focus is on the target enzyme Plasmodium falciparum enoyl ACP reductase (Pf ENR), validated as an effective target for several licensed antimicrobials. This is a "Hits to Lead" program that builds on a high throughput screen against Pf ENR, in order that we can define several pharmacologically active lead compounds for preclinical development. Project 1 (Sacchettini, project leader (PL) and Garcia-Bustos, Co-PL) will focus on the high-throughput screening (HTS), the development of a structure activity relationship for several classes of compounds and the synthesis of new lead compounds. The Sacchettini lab will be responsible for the X-ray crystal structures of the enzyme target with inhibitors and the design of new compounds based on the crystal structure. The Garcia-Bustos lab and other groups at GSK will be responsible for the HTS and ensuing synthetic and medicinal chemistry, including a thorough work-up of PK, PD, ADME and toxicity for lead compounds. Project 2 (Fidock, PL) will conduct whole cell assays of these compounds against P. falciparum as well as efficacy studies in the P. berghei malaria mouse model, including the development and use of transgenic P. falciparum and P. berghei parasites to better correlate in vitro and in vivo data and also to develop a new means of screening inhibitors for efficacy against P. vivax (the second most important human malaria parasite). Project 3 (Jacobs, PL) will use genetic tools to develop transgenic mouse malaria models and determine modes of activity and resistance of new compounds using Escherichia coli and Plasmodium model systems. All of the investigators have track records for successful and productive collaborations and will consult with and share physical and intellectual resources. The information gained from these studies will provide new clinical candidates to treat malaria infections.